Invasive fungal infections (IFIs) have become prominent global health threats, escalating the burden on public health systems. The increasing occurrence of invasive fungal infections is due primarily to the extensive application of chemotherapy, immunosuppressive therapies, and broad-spectrum antifungal agents. At present, therapeutic practices utilize multiple categories of antifungal agents, such as azoles, polyenes, echinocandins, and pyrimidine analogs. Nevertheless, the clinical effectiveness of these treatments is progressively weakened by the emergence of drug resistance, thereby substantially restricting their therapeutic utility. Consequently, there is an imperative need to expedite the discovery of novel antifungal agents. This review seeks to present an exhaustive synthesis of novel antifungal drugs and candidate agents that are either under current clinical investigation or anticipated to progress into clinical evaluation. These emerging compounds exhibit unique benefits concerning their modes of action, antimicrobial spectra, and pharmacokinetic characteristics, potentially leading to improved therapeutic outcomes relative to conventional antifungal regimens. It is anticipated that these novel therapeutic agents will furnish innovative treatment modalities and enhance clinical outcomes in managing invasive fungal infections.

Prostate cancer is the most prevalent malignant tumor among men, ranking first in incidence and second in mortality globally. Novel hormone therapies (NHT) targeting the androgen receptor (AR) pathway have become the standard of care for metastatic prostate cancer. This review offers a comprehensive overview of NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, and rezvilutamide, which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life. Nevertheless, resistance to NHT remains a critical challenge. The mechanisms underlying resistance are complex, involving AR gene amplification, mutations, splice variants, increased intratumoral androgens, and AR-independent pathways such as the glucocorticoid receptor, neuroendocrine differentiation, DNA repair defects, autophagy, immune evasion, and activation of alternative signaling pathways. This review discusses these resistance mechanisms and examines strategies to counteract them, including sequential treatment with novel AR-targeted drugs, chemotherapy, poly ADP-ribose polymerase inhibitors, radionuclide therapy, bipolar androgen therapy, and approaches targeting specific resistance pathways. Future research should prioritize elucidating the molecular basis of NHT resistance, optimizing existing therapeutic strategies, and developing more effective combination regimens. Additionally, advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies. These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.

OBJECTIVE To investigate the inhibitory effect and mechanism of the active components of Alpinia katsumadai （ACAK） on tumor xenograft growth and tumor angiogenesis of human pancreatic cancer PANC-1 cells in nude mice. METHODS A tumor xenograft model in nude mice was established using human pancreatic cancer PANC-1 cells. The mice were randomly divided into model control group （intragastric administration of 0.9% normal saline）， solvent control group （intragastric administration of 0.5% carboxymethyl cellulose sodium）， positive control group （intraperitoneal injection of 0.5% carboxymethyl cellulose sodium+bevacizumab suspension 5 mg/kg ）， and ACAK 50， 100， and 200 mg/kg groups （intragastric administration of 0.5% carboxymethyl cellulose sodium+ACAK suspension 50， 100， 200 mg/kg）. The administration was carried out for 5 consecutive days followed by a 2-day interval， and this cycle was repeated for a total duration of 28 days. The tumor volume （TV）， relative tumor volume （RTV）， and relative tumor proliferation rate （T/C） at various time points from day 1 to day 28 after drug administration were measured and calculated for each group of nude mice. After the drug administration， the tumor weights were measured， and microvessel density （MVD） in the tumor xenograft tissues of nude mice， as well as relative protein expression levels of vascular endothelial growth factor （VEGF） and its receptor [fas-like tyrosine kinase-1 （Flt-1）， kinase insert domain receptor （KDR）] were detected. RESULTS On the 24th day of ACAK administration，compared with the model control group， the TV and RTV （except for ACAK 50 and 100 mg/kg groups） of nude mice in the positive control group and ACAK dose groups were significantly decreased （P＜0.05 or P＜0.01）， and the T/C of ACAK dose groups showed a dose-dependent decrease； the microvascular distribution of nude mice in the positive control group and ACAK dose groups was relatively sparse， and the tumor weight （except for the ACAK 50 mg/kg group）， MVD， and relative expression levels of VEGF， KDR， and Flt-1 in the tumor xenograft tissues were significantly reduced （P＜0.05 or P＜0.01）. CONCLUSIONS ACAK has a good anti-pancreatic cancer effect， and its mechanism may be related to its inhibition of VEGF/ VEGFR signaling pathway， thereby inhibiting angiogenesis in pancreatic cancer.

Background Occupational stress has emerged as a critical public health concern affecting the physical and mental well-being of workers in the manufacturing sector. However, researchers typically evaluate its core driver—cumulative fatigue—using a crude binary “present/absent” variable, thereby overlooking the high-dimensional complexity and heterogeneity inherent in fatigue characteristics. This oversimplification constrains both the precision and predictive performance of occupational stress risk assessment model. Objective Leveraging a data-driven approach, to survey data on cumulative fatigue among manufacturing employees, and then use this new classification to develop and validate an occupational stress prediction model, with an ultimate aim of enhancing the accuracy and effectiveness of occupational stress assessment. Methods A set of cross-sectional survey data on 3871 manufacturing employees in 2021 were derived from the “Long working hours exposure and its adverse health effect risk assessment” program of the National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention. Occupational stress was assessed using the Core Occupational Stress Measurement Scale, while cumulative fatigue was evaluated via the Worker’s Self-Diagnostic Questionnaire for Fatigue Accumulation. Boruta method was applied to screen core variables from 20 occupational stress influencing factors. Dimensionality reduction of cumulative fatigue features was performed using a Bayesian sparse autoencoder (BASE), followed by comparison and application of clustering methods to achieve multi-class classification of the reduced features. Six machine learning classification models were then selected including logistic regression, support vector machine, decision tree, random forest, adaptive boosting, and lightweight gradient boosting machine (LightGBM) to construct and compare two occupational stress prediction models involving cumulative fatigue combined with ten other core variables: one utilizing the original binary cumulative fatigue label as a core variable, and another employing the novel fatigue classification proposed herein as a core variable. Results The positive rate of occupational stress among the manufacturing employees was 38.9%. The Boruta method identified 11 core variables of occupational stress: depressive symptoms, cumulative fatigue, age, length of service, tenure in current position, average weekly working hours, average daily overtime hours, average monthly income, low levels of exercise, life satisfaction, and sleep quality. The BSAE reduced the original cumulative fatigue factors to 12 dimensions, while the K-means clustering grouped the reduced fatigue features into three categories: no fatigue, moderate fatigue, and sever fatigue. Six occupational stress prediction models were constructed using the three-category labels of cumulative fatigue and ten additional factors. The results indicated that the LightGBM model performed best, achieving an area under the curve (AUC) of 0.78, an accuracy of 0.77, and an F1 score of 0.72. Compared with the model incorporating the traditional binary labels for cumulative fatigue, the best prediction AUC (0.72), accuracy (0.66), and F1 score (0.65) improved by 6%, 11%, and 7%, respectively. Conclusion Cumulative fatigue is a significant predictor of occupational stress among manufacturing employees. Applying data dimensionality reduction combined with three-class cluster analysis to characterize cumulative fatigue improves the performance of occupational stress prediction models. From a data-driven perspective, machine learning methods demonstrate strengths in processing complex datasets, capturing nonlinear relationships, and generating predictions based on key variables. This study therefore confirms that refined processing of core factors substantially enhances the predictive capability of machine learning models in assessing occupational stress risk in the manufacturing workforce.

Objective To investigate the effects of an adeno-associated virus(AAV2)vector expressing secretory transforming growth factor-β(TGF-β)type Ⅱ receptor(sTβRⅡ)extracellular domain-IgG2a Fc fusion protein(sTβRⅡ-Fc)on proliferation and migration of triple-negative murine breast cancer 4T1 cells in mice.Methods The pAAV-sTβRⅡ-Fc vector expressing sTβRⅡ-Fc fusion protein constructed by molecular cloning,the capsid protein-expressing vector pAAV2 and the helper vector were co-transfected into HEK 293T cells to prepare the recombinant AAV2-sTβRⅡ virus,which was purified by density gradient centrifugation with iodixanol.Western blotting was used to examine the effects of AAV-sTβRⅡ virus on Smad2/3 phosphorylation in 4T1 cells and on expression levels of E-cadherin,vimentin and p-Smad2/3 in 4T1 cell xenografts in mice.BALB/c mice bearing subcutaneous xenografts of luciferase-expressing 4T1 cells received intravenous injections of AAV-sTβRⅡ virus,AAV-GFP virus or PBS(n=6)through the tail vein,and the proliferation and migration of 4T1 cells were analyzed with in vivo imaging.Ki67 expression in the tumor tissues and sTβRⅡ protein expressions in mouse livers were detected with immunohistochemistry and immunofluorescence staining,and tumor metastases in the vital organs were examined with HE staining.Results The recombinant pAAV-sTβRⅡ-Fc vector successfully expressed sTβRⅡ in HEK 293T cells.Infection with AAV2-sTβRⅡ virus significantly reduced TGF-β1-induced Smad2/3 phosphorylation in 4T1 cells and effectively inhibited proliferation and lung metastasis of 4T1 xenografts in mice(P<0.05).In the tumor-bearing mice,intravenous injection of AAV-sTβRⅡ virus significantly increased E-cadherin expression,reduced vimentin and Ki67 protein expressions and Smad2/3 phosphorylation level in the tumor tissues(P<0.05 or 0.01),and induced liver-specific sTβRⅡ expression without causing body weight loss or heart,liver,spleen or kidney pathologies.Conclusion The recombinant AVV2 vector encoding sTβRⅡ extracellular domain is capable of blocking the TGF-β signaling pathway to inhibit the proliferation and lung metastasis of 4T1 cells in mice.

Objective To investigate the effects of an adeno-associated virus(AAV2)vector expressing secretory transforming growth factor-β(TGF-β)type Ⅱ receptor(sTβRⅡ)extracellular domain-IgG2a Fc fusion protein(sTβRⅡ-Fc)on proliferation and migration of triple-negative murine breast cancer 4T1 cells in mice.Methods The pAAV-sTβRⅡ-Fc vector expressing sTβRⅡ-Fc fusion protein constructed by molecular cloning,the capsid protein-expressing vector pAAV2 and the helper vector were co-transfected into HEK 293T cells to prepare the recombinant AAV2-sTβRⅡ virus,which was purified by density gradient centrifugation with iodixanol.Western blotting was used to examine the effects of AAV-sTβRⅡ virus on Smad2/3 phosphorylation in 4T1 cells and on expression levels of E-cadherin,vimentin and p-Smad2/3 in 4T1 cell xenografts in mice.BALB/c mice bearing subcutaneous xenografts of luciferase-expressing 4T1 cells received intravenous injections of AAV-sTβRⅡ virus,AAV-GFP virus or PBS(n=6)through the tail vein,and the proliferation and migration of 4T1 cells were analyzed with in vivo imaging.Ki67 expression in the tumor tissues and sTβRⅡ protein expressions in mouse livers were detected with immunohistochemistry and immunofluorescence staining,and tumor metastases in the vital organs were examined with HE staining.Results The recombinant pAAV-sTβRⅡ-Fc vector successfully expressed sTβRⅡ in HEK 293T cells.Infection with AAV2-sTβRⅡ virus significantly reduced TGF-β1-induced Smad2/3 phosphorylation in 4T1 cells and effectively inhibited proliferation and lung metastasis of 4T1 xenografts in mice(P<0.05).In the tumor-bearing mice,intravenous injection of AAV-sTβRⅡ virus significantly increased E-cadherin expression,reduced vimentin and Ki67 protein expressions and Smad2/3 phosphorylation level in the tumor tissues(P<0.05 or 0.01),and induced liver-specific sTβRⅡ expression without causing body weight loss or heart,liver,spleen or kidney pathologies.Conclusion The recombinant AVV2 vector encoding sTβRⅡ extracellular domain is capable of blocking the TGF-β signaling pathway to inhibit the proliferation and lung metastasis of 4T1 cells in mice.

The cognitive impairment of diabetes mellitus type 2(T2DM)is closely related to neurovascular coupling(NVC)changes,but the exact mechanism remains unclear.Functional MRI(fMRI)technology were able to jointly analyze NVC changes of T2DM,providing new ideas for revealing the mechanism of cognitive dysfunction caused by T2DM.The progresses of fMRI for exploring NVC changes in T2DM were reviewed in this article.

Objective:To retrieve, evaluate and integrate the relevant evidence of prevention of lower limb ischemic complications in venous-arterial extracorporeal membrane oxygenation (VA-ECMO) patients, and provide reference for the development of scientific and complete prevention and management of lower limb ischemic complications.Methods:According to the evidence-based methodology, clinical decisions, guidelines, expert consensus, evidence summary, systematic review, randomized controlled trials and experimental studies related to lower limb ischemia complications in VA-ECMO patients were searched from CNKI, Wanfang, PubMed, Cochrane Library and other domestic and foreign databases as well as relevant professional websites. The literature search period was from the establishment of the database to August 2023. Two researchers independently evaluated the literature quality, and then extracted and summarized the evidence according to the theme.Results:A total of 27 004 articles were obtained in the preliminary search, and 11 articles were finally included after screening, including 1 guide, 2 expert consensus, 2 systematic reviews and 6 original studies. Through literature reading, evidence extraction and classification, and expert group meetings, a total of 24 best evidences were concluded in four dimensions, including team training and management, VA-ECMO pre-computer evaluation, VA-ECMO catheter selection, and the monitoring and management of lower limb ischemia.Conclusions:This study summarized the best evidence for the prevention of lower limb ischemia complications associated with VA-ECMO patients, and can provide reference for healthcare providers in clinical practice. In order to ensure the safety of VA-ECMO treatment and reduce the incidence of related complications, healthcare professionals should carefully select and apply evidence according to the clinical context and patients′ wishes.

Objective:To investigate the clinical effect of orbital septal fascia advancement in the correction of mild blepharoptosis.Methods:From December 2016 to January 2020, a total of 77 eyes of 56 patients with mild congenital ptosis who underwent double eyelid surgery were treated. The method of orbital septal fascia advancement was used to correct mild ptosis. Specifically, during double eyelid reconstruction, the orbital septum was opened and the orbital septal fascia about 2 mm in front of the fold was preserved. The posterior lip of the orbital septal fascia was pulled down to the upper part of the tarsal plate, and fixed on the tarsal plate with 3 stitches of 5-0 nylon suture, and appropriate adjustments were made to correct mild ptosis.Results:Patients (56 eyes of 40 cases) were followed up from 6 to 12 months (average 7.4 months), 46 eyes (82.1%) were satisfied with blepharoptosis correction, 8 eyes (14.3%) were basically satisfied with blepharoptosis correction, and 2 eyes (3.6%) were dissatisfied with blepharoptosis correction. 45 eyes (80.4%) were satisfied with blepharoplasty, 7 eyes (12.5%) were basically satisfied with blepharoplasty, and 4 eyes (7.1%) were dissatisfied with blepharoplasty. No double eyelid folds disappeared after surgery, and there were no complications such as incomplete closure, conjunctival prolapse, or exposed keratitis.Conclusions:The correction effect of blepharoptosis is good, and the reconstruction structure is stable with natural appearance, fast recovery and high satisfaction. Therefore, the method can be popularized.

To analyze the long-term stability of the output dose of the medical linear accelerator VitalBeam based on Mechanical Performance Check(MPC)system.500 daily self-test data of the medical linear accelerator VitalBeam from January 2021 to December 2023 were collected,and the change trend and stability status of dose output deviation were analyzed.Through MPC detection and data analysis,the 6MV X-Ray in radiation dose output change was(0.53±0.85)%,the ray uniformity change was(0.54±0.15)%,and the ray center offset change was(0.15±0.07)mm,all of which were within the allowable range of error.The 6 MV photon beam dose output of the medical linear accelerator is stable and reliable,which meets the needs of clinical treatment,and the MPC detection can be used for the daily inspection and quality control of the accelerator.